Elucidating a Tumor-Selective Nanoparticle Delivery Mechanism at the Colorectal Lumen-Tumor Interface for Precise Local Cancer Therapy.

Although various colorectal cancer (CRC)-targeted nanoparticles have been developed to selectively deliver anticancer agents to tumor tissues, severe off-target side effects still persist due to unwanted systemic nanoparticle distribution, limiting the therapeutic outcome. Here, by elucidating a tumor-selective nanoparticle delivery mechanism occurring at the colorectal lumen-tumor interface, an alternative CRC-targeted delivery route is proposed, which enables highly tumor-selective delivery without systemic distribution, through direct drug delivery from the outside of the body (colorectal lumen) to tumors in the colorectum. Owing to the presence of accessible tumor-specific receptors such as CD44 at the colorectal lumen-tumor interface, but not at the colorectal lumen-normal tissue interface, colorectal luminal surface (CLS)-targeting ligand-functionalized nanoparticles selectively accumulate in CRC tissues without systemic distribution, resulting in successful local CRC therapy. The findings suggest that CLS-targeted lumen-to-tumor delivery can be a suitable strategy for highly CRC-specific drug delivery for precise local CRC therapy.